WHO recommends RTS,S/AS01 as the world’s first malaria vaccine
Malaria remains a major public health challenge in sub-Saharan Africa (SSA) despite the global gains made in recent years.1 In 2022, about 249 million malaria cases were reported, with 94% of cases and 95% of deaths occurring in the WHO African region.2 Children are among the most vulnerable populations as they are at higher risk of malaria infection and related complications. While malaria deaths in children aged under 5 years fell from 87% in 2000 to 76% in 2015, progress has stalled, with 78% of all malaria deaths in the WHO African region in 2022 among children under 5 years.2
In October 2021, the WHO recommended the RTS,S/AS01 (Mosquirix; GlaxoSmithKline (GSK)) malaria vaccine for the prevention of Plasmodium falciparum malaria in children living in regions with moderate-to-high malaria transmission.3 This followed more than four decades of basic research and clinical trials.4 The RTS,S/AS01 vaccine, extensively tested in different endemic regions in Africa, has moderate efficacy, reducing clinical malaria in children aged 6 weeks to 18 months by 46% (95% CI 41.7% to 49.5%) and severe disease by 36% (95% CI 14.6% to 51.1%) 18 months after the third dose.5 Though the effect is short lived and may depend on the transmission intensity, the vaccine also confers protection to HIV-infected children for up to 1 month after the third dose.6–8 The WHO recommends a four-dose vaccine schedule with a three-dose primary series given at a minimum interval of 4 weeks between doses in children from 5 months of age, with a fourth dose 12–18 months after the third dose to prolong the duration of protection.3 There is a provision for a seasonal five-dose strategy in areas of highly seasonal malaria or with perennial malaria transmission with seasonal peaks, as the HR for the protective efficacy of seasonal vaccination compared with chemoprevention was 0.92 (95% CI 0.84 to 1.01).3 9 The vaccine reduced clinical malaria by 46% (95% CI 41.8% to 50.1%) and by 34% (95% CI 28.9% to 38.6%) over a period of 3–4 years when administered with or without the fourth booster dose, respectively.10 It has been shown to reduce all-cause mortality (excluding injury) by 13% (0.87, 95% CI 0.78 to 0.98) and hospitalisation due to severe malaria by 22% (0.78, 95% CI 0.64 to 0.96), during the 46 months of its introduction.11 12
In 2015, the European Medicines Agency (EMA) gave RTS,S/AS01 a positive recommendation after reviewing the efficacy data from large phase III trials.10 Following the EMA recommendation, the WHO recommended its pilot implementation in three countries to determine the impact on the incidence of hospital admission with severe malaria, all-cause mortality and meningitis or cerebral malaria after a possible association was detected in the phase III trials in addition to the feasibility of implementing the recommended four doses in the context of routine health systems.13 14 The WHO evaluation was to be conducted over 4 years; however, sufficient data had accrued after 24 months, in October 2021, for WHO to make a recommendation. The evaluation confirmed the vaccine’s safety and demonstrated the feasibility of implementation within the existing Essential Programme on Immunization (EPI) in resource-limited settings.15
Despite recent progress with RTS,S/AS01, its efficacy falls well below WHO’s strategic goal set in 2013: ‘By 2030, licensed malaria vaccines should have 75% or higher vaccine efficacy against clinical malaria with duration of protection demonstrated over at least two years’.16 A second malaria vaccine, R21/Matrix-M, developed by the University of Oxford, UK and recommended by the WHO for widespread use in October 2023, was the first to achieve the WHO-specified targets with a vaccine efficacy of 78% (95% CI 71% to 83%) in the second year of follow-up following three primary series doses and a booster dose administered seasonally in phase II trials.17–19 R21/Matrix-M was added to the WHO prequalified vaccines list in December 2023 and is expected to be available in mid-2024.12 20 Results from phase III trials showed R21/Matrix-M reduced clinical malaria cases by 72% (95% CI 69% to 75%) after three primary series doses and a booster dose.21 The trial is ongoing, and additional information, such as differences between the standard age-based regimen and seasonal administration after 24 months of follow-up, will be known after quarter 1 of 2024.22 The WHO recommends a three-dose primary series of the R21/Matrix-M vaccine given at a minimum interval of 4 weeks between doses in children from 5 months of age, with flexibility on when the fourth dose is delivered, similar to the RTS,S/AS01 regimen.19 A fifth dose may be considered in areas of significant risk, and countries may consider providing the vaccine using age-based, seasonal or hybrid delivery strategies in areas with highly seasonal malaria or areas with perennial malaria transmission with seasonal peaks. The WHO recommends that countries prioritise vaccination with RTS,S/AS01 and R21/Matrix-M in moderate and high transmission areas but may also consider providing the vaccine in low transmission settings.12 Other vaccine candidates are in development, most in phase I and preclinical stages, with more than 100 ongoing studies as of 2021.23 Notably, the PfSPZ vaccine is approaching late-stage clinical evaluation.3 24 25
This analysis describes the status of malaria vaccine registration, policy uptake and implementation, two years following the registration of the first vaccine.